N-amino-morpholine hydrochloride → 4-[(1R,2E,4R,5S,8S,12R)-4-methyl-2-morpholin-4-ylimino-6-oxo-9,13-dioxa-7-azatetracyclo[6.3.1.11,4.05,12]tridecan-7-yl]-2-(trifluoromethyl)benzonitrile

HRID 563907Notes

Reaction equation

O[C@H:2]1[CH2:12][C@@:11]2([CH3:14])[O:13][C@@:3]31[C@@H:15]1[C@@H:7]([N:8]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=4)[C:9](=[O:16])[C@H:10]21)[O:6][CH2:5][CH2:4]3.Cl.[NH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>N1C=CC=CC=1.CCOC(C)=O>[CH3:14][C@:11]12[O:13][C@:3]3([C@@H:15]4[C@@H:7]([N:8]([C:17]5[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:26])([F:28])[F:27])[CH:18]=5)[C:9](=[O:16])[C@H:10]14)[O:6][CH2:5][CH2:4]3)/[C:2](=[N:30]/[N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)/[CH2:12]2

Participants

Conditions

Temperature: 50 °C

Procedure

To a stirring solution of Example 3 (85 mg, 0.216 mmol) in pyridine (2 mL) was added. N-aminomorpholine hydrochloride (0.287 mmol, 1.5 eq). The mixture was stirred at 50° C. for 1 h. The reaction was judged completed by LCMS. The reaction mixture was cooled to room temperature. It was then diluted with EtOAc (6 ml) and extracted with 1N HCl (2×10 ml). The ethyl acetate layer was then washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified on Isco (12 g column) 0-5% MeOH-DCM to give Example 92 (59 mg, 58%, 0.133 mmol).

Workup

temperatureThe reaction mixture was cooled to room temperature
extractionextracted with 1N HCl (2×10 ml)
washThe ethyl acetate layer was then washed with brine
dry with materialdried over anhydrous sodium sulfate
filtrationfiltered
concentrationconcentrated under reduced pressure
customThe crude was purified on Isco (12 g column) 0-5% MeOH-DCM

Sources & evidence

ORD record: ord-745ba4fd06154d2ea01ff42a7f25dd20
Source dataset: uspto-grants-2011_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08067582B2

Reaction notes

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